Many synthetic materials have been medically used in the body, including polyester (e.g., DACRON™), polyethylene (e.g., milk jugs), and fluorocarbons (e.g., TEFLON™), and metals. A patient's body responds by treating a synthetic material as an invader, although it responds only mildly in some medical applications; for example, a metal hip implant is generally well tolerated. One common response to an implant is called a foreign body response in which the body forms a capsule of cells around the material; the body's response to a splinter is a foreign body response. When synthetic material is used as an artificial blood vessel, for example, the blood that flows through the artificial blood vessel reacts with the synthetic material. The reaction can cause clots to form that flow downstream that may eventually become stuck in a smaller vessel; if this happens in the brain, it is called a stroke. The blood clot can also grow on the inside of the vessel and block or severely restrict the blood flow. Blood's clotting mechanism is highly reactive and, despite years of medical research, no implantable blood-contacting synthetic material has yet been found that does not cause blood to react.
Tubes made of polyester or fluorocarbons are currently used as large diameter blood vessels. The blood clots onto the interior walls and reduces the inside diameter of the vessel but the blood flow is not unduly reduced. The blood clot on the tubular wall serves as a protective layer that elicits very little reaction from blood flowing through the vessel. This approach, however, does not work for small diameter blood vessels because the small diameter tubes are blocked when the blood clots onto the walls.
There are no currently known materials and techniques for manufacturing small diameter vascular grafts made of synthetic materials. Unfortunately, there is a great need for such grafts. One example is the condition called deep vein thrombosis wherein a patient's veins become blocked. The blood drains poorly from the leg and amputation can result. Unlike heart bypass surgeries where the patient often has some blood vessels that can be harvested from elsewhere in the body and sewn into place, there are few choices for replacing the long veins of the leg.
One area of synthetic biomaterials research has focused on hydrogels, materials that have a high water content and are soft and slippery. Soft contact lenses are examples of hydrogels. The materials used to make a pure hydrogel might all dissolve in water but the hydrogel itself does not dissolve in water because the materials are cross-linked; in other words, the individual molecular chains are linked together like the strands in a net or a spider's web. Hydrogels tend to elicit a milder foreign body response than other synthetic materials. Some hydrogel biomaterials that are currently considered to be commercially useful are made from polyethylene glycol (PEG), hyaluronic acid, and alginates. Although hydrogels tend to elicit less blood clotting than other synthetic materials, hydrogels have not previously been successfully used to make a small diameter vascular graft.
Scientists have also tried to use heparin to coat the inside of vascular grafts made of synthetic materials. Heparin is a molecule that belongs to a group of molecules called polysaccharides that are polymers made from combinations of sugar monomers. There are many sugars; glucose and sucrose (table sugar) are two examples. Polysaccharides are naturally-occurring polymers. Polymers are molecules built up by the repetition of smaller units that are sometimes called monomers. Polymers are typically made by special chemical schemes that make the monomers chemically react with each other to form molecular chains that can range in length from short to very long molecules. Polymers can be assembled into larger materials; for example, many polymers may be linked together to form a hydrogel.
Heparin is a polysaccharide polymer with an important property: it interferes with key molecules in the blood clotting mechanism such that the blood will not clot. Coating the inside of a synthetic material tube with heparin tends to increase the amount of time that the tube remains open to blood flow but, to date, small diameter vascular grafts coated with heparin have failed to resist blockage by blood clots for a medically useful length of time.
Heparin has been applied to materials in many ways. General strategies include letting it naturally stick to a surface (termed adsorption), making a charge-charge bond with the surface (e.g., an ionic bond), and attaching it via an even stronger, more permanent chemical linkage such as a covalent bond. Heparin has been applied as a thin coating of polymers adsorbed to a surface by dipping the surface into a solution of heparin or drying the heparin onto the surface. Heparin has a negative charge and has been exposed to surfaces that have a positive charge so that it remains there via a charge-charge interaction. Photoactivated chemical groups have been put onto heparin so that the heparin is put close to the surface, the surface is bathed in light, and the photoactive groups make permanent covalent chemical bonds between the heparin polymer and the surface. Similarly, heparin has been chemically attached to monomers that have then been reacted with the surface.
Patent families and patent applications that describe the use of heparin include U.S. Pat. No. 6,127,348, which include descriptions of cross-linked alginate and certain other polysaccharides as compositions useful for inhibiting fibrosis. U.S. Pat. No. 6,121,027 includes descriptions of decorating heparin with a photoactive cross linking chemical group. Application PCT GB9701173 and U.S. Pat. No. 6,096,798 include descriptions of heparins with monomers used to make polymers. U.S. Pat. Nos. 5,763,504 and 5,462,976 include descriptions of glycosaminoglycans derivatized with photoactive groups and cross-linked thereby. U.S. Pat. No. 6,060,582 includes descriptions of macromers with a water soluble region, a biodegradable region, and at least two free-radical polymerizable regions. Other patents include descriptions of a polysaccharide reacted with other polymers, decorated with a polymerizable group, and/or reacted to form a coating on a surface; including U.S. Pat. Nos. 5,993,890; 5,945,457; 5,877,263; 5,855,618; 5,846,530; 5,837,747; 5,783,570; 5,776,184; 5,763,504; 5,741,881; 5,741,551; 5,728,751; 5,583,213; 5,512,329; 5,462,976; 5,344,455; 5,183,872; 4,987,181; 4,331,697; 4,239,664; 4,082,727; and European patents 049,828 A1 & B1.
Despite many years of research in the areas of polysaccharides, hydrogels, and blood-contacting materials, the need for better implantable synthetic materials that cause little or no unfavorable reaction from a patient's body remains acute. In particular, there is a great need for a medically useful small diameter vascular graft made of synthetic materials.